BACKGROUND: Androgen-receptor pathway inhibitors (ARPIs) have dramatically changed the management of advanced/metastatic prostate cancer (PCa). However, their cardiovascular toxicity remains to be clarified. OBJECTIVE: To analyze and compare the risks of cardiovascular events secondary to treatment of PCa patients with different ARPIs. METHODS: In August 2023, we queried PubMed, Scopus, and Web of Science databases to identify randomized controlled studies (RCTs) that analyze PCa patients treated with abiraterone, apalutamide, darolutamide, and enzalutamide. The primary outcomes of interest were the incidence of cardiac disorder, heart failure, ischemic heart disease (IHD), atrial fibrillation (AF), and hypertension. Network meta-analyses (NMAs) were conducted to compare the differential outcomes of each ARPI plus androgen deprivation therapy (ADT) compared to standard of care (SOC). RESULTS: Overall, 26 RCTs were included. ARPIs were associated with an increased risk of cardiac disorders (RR: 1.74, 95% CI: 1.13-2.68, p = 0.01), heart failure (RR: 2.49, 95% CI: 1.05-5.91, p = 0.04), AF (RR: 2.15, 95% CI: 1.14-4.07, p = 0.02), and hypertension (RR: 2.06, 95% CI: 1.67-2.54, p < 0.01) at grade ≥3. Based on NMAs, abiraterone increased the risk of grade ≥3 cardiac disorder (RR:2.40, 95% CI: 1.42-4.06) and hypertension (RR:2.19, 95% CI: 1.77-2.70). Enzalutamide was associated with the increase of grade ≥3 AF(RR: 3.17, 95% CI: 1.05-9.58) and hypertension (RR:2.30, 95% CI: 1.82-2.92). CONCLUSIONS: The addition of ARPIs to ADT increases the risk of cardiac disorders, including IHD and AF, as well as hypertension. Each ARPI exhibits a distinct cardiovascular event profile. Selecting patients carefully and vigilant monitoring for cardiovascular issues is imperative for those undergoing ARPI + ADT treatment.

• MeSH
• Androgen Receptor Antagonists * adverse effects   therapeutic use   MeSH
• Benzamides adverse effects   MeSH
• Cardiovascular Diseases * chemically induced   epidemiology   MeSH
• Humans MeSH
• Prostatic Neoplasms * drug therapy   pathology   MeSH
• Nitriles adverse effects   MeSH
• Randomized Controlled Trials as Topic MeSH
• Check Tag
• Humans MeSH
• Male MeSH
• Publication type
• Journal Article MeSH
• Network Meta-Analysis MeSH
• Systematic Review MeSH
• Names of Substances
• abiraterone MeSH Browser
• Androstenes MeSH
• Androgen Receptor Antagonists * MeSH
• Benzamides MeSH
• enzalutamide MeSH Browser
• Phenylthiohydantoin MeSH
• Nitriles MeSH

Purpose: The addition of androgen receptor pathway inhibitors (ARPIs) to androgen deprivation therapy (ADT), with or without docetaxel (Doc), is currently recommended for metastatic, hormone-sensitive prostate cancer (mHSPC). Recently, the ARANOTE trial evaluated the efficacy and safety of Darolutamide + ADT in this setting. We aimed to update a network meta-analysis (NMA) of these combination therapies. Methods: We conducted a systematic search for RCTs on systemic therapies for mHSPC using MEDLINE, Embase, and the Web of Science Core Collection in September 2024. An NMA utilizing random-effects models was performed to compare progression-free survival (PFS), overall survival (OS), and adverse event (AE) incidence (PROSPERO: CRD42024591458). Results: A total of 12 RCTs (n = 11,954) were included in our NMAs. Triplet therapies were associated with significant improvements in PFS compared to ARPI-based doublet therapies (hazard ratio [HR]: 0.74; 95% confidence interval [CI]: 0.59-0.93; p = 0.01), but the difference did not reach the conventional levels of statistical significance for OS (HR: 0.82; 95% CI: 0.67-1.01; p = 0.059). In a subset analysis, compared to ARPI-based doublet therapies, triplet therapies showed a significant improvement in PFS in patients with high-volume disease (HR: 0.64; 95% CI: 0.47-0.88; p < 0.01), whereas no significant improvement was observed in those with low-volume disease (HR: 0.86; 95% CI: 0.45-1.67; p = 0.7). No significant difference in grade ≥ 3 AEs was observed between triplet therapies and ARPI-based doublet therapies. The main limitations include patient heterogeneity and limited follow-up in some studies. Conclusions: Triplet therapies can improve the oncologic outcomes of patients with mHSPC compared to ARPI-based doublet therapies, without significantly increasing severe AEs. These findings warrant further confirmation in a head-to-head trial powered for overall survival.

• Keywords
• ARPI, adverse event, docetaxel, mHSPC, network meta-analysis, overall survival, progression-free survival, systematic review, triplet therapy,
• Publication type
• Journal Article MeSH
• Review MeSH

BACKGROUND: Triplet therapy, androgen receptor signaling inhibitors (ARSIs) plus docetaxel plus androgen-deprivation therapy (ADT), is a novel guideline-recommended treatment for metastatic hormone-sensitive prostate cancer (mHSPC). However, the optimal selection of the patient most likely to benefit from triplet therapy remains unclear. METHODS: We performed a systematic review, meta-analysis, and network meta-analysis to assess the oncologic benefit of triplet therapy in mHSPC patients stratified by disease volume and compare them with doublet treatment regimens. Three databases and meeting abstracts were queried in March 2023 for randomized controlled trials (RCTs) evaluating patients treated with systemic therapy for mHSPC stratified by disease volume. Primary interests of measure were overall survival (OS). We followed the PRISMA guideline and AMSTAR2 checklist. RESULTS: Overall, eight RCTs were included for meta-analyses and network meta-analyses (NMAs). Triplet therapy outperformed docetaxel plus ADT in terms of OS in both patients with high-(pooled HR: 0.73, 95%CI 0.64-0.84) and low-volume mHSPC (pooled HR: 0.71, 95%CI 0.52-0.97). There was no statistically significant difference between patients with low- vs. high-volume in terms of OS benefit from adding ARSI to docetaxel plus ADT (p = 0.9). Analysis of treatment rankings showed that darolutamide plus docetaxel plus ADT (90%) had the highest likelihood of improved OS in patients with high-volume disease, while enzalutamide plus ADT (84%) had the highest in with low-volume disease. CONCLUSIONS: Triplet therapy improves OS in mHSPC patients compared to docetaxel-based doublet therapy, irrespective of disease volume. However, based on treatment ranking, triplet therapy should preferably be considered for patients with high-volume mHSPC while those with low-volume are likely to be adequately treated with ARSI + ADT.

• Keywords
• Androgen receptor signaling inhibitor, Docetaxel, High-volume, Low-volume, Metastatic hormone-sensitive prostate cancer,
• MeSH
• Androgen Receptor Antagonists therapeutic use   MeSH
• Androgen Antagonists * therapeutic use   MeSH
• Docetaxel * therapeutic use   administration & dosage   MeSH
• Humans MeSH
• Prostatic Neoplasms * drug therapy   mortality   pathology   MeSH
• Antineoplastic Combined Chemotherapy Protocols * therapeutic use   MeSH
• Randomized Controlled Trials as Topic MeSH
• Tumor Burden MeSH
• Check Tag
• Humans MeSH
• Male MeSH
• Publication type
• Journal Article MeSH
• Network Meta-Analysis MeSH
• Systematic Review MeSH
• Names of Substances
• Androgen Receptor Antagonists MeSH
• Androgen Antagonists * MeSH
• Docetaxel * MeSH

(1) Background: Several phase II studies, including randomized controlled trials (RCTs), assessed the efficacy of adding androgen receptor signaling inhibitors (ARSIs) to androgen deprivation therapy (ADT) as a neoadjuvant treatment in patients treated with radical prostatectomy (RP) for prostate cancer (PCa). Summarizing the early results of these studies could help in designing phase III trials and patient counseling. (2) Methods: We queried three databases in January 2023 for studies that included PCa patients treated with neoadjuvant ARSI-based combination therapy before RP. The outcomes of interest were oncologic outcomes and pathologic responses, such as pathologic complete response (pCR) and minimal residual disease (MRD). (3) Results: Overall, twenty studies (eight RCTs) were included in this systematic review. Compared to ADT or ARSI alone, ARSI + ADT was associated with higher pCR and MRD rates; this effect was less evident when adding a second ARSI or chemotherapy. Nevertheless, ARSI + ADT resulted in relatively low pCR rates (0-13%) with a high proportion of ypT3 (48-90%) in the resected specimen. PTEN loss, ERG positive, or intraductal carcinoma seem to be associated with worse pathologic response. One study that adjusted for the effects of possible confounders reported that neoadjuvant ARSI + ADT improved time to biochemical recurrence and metastasis-free survival compared to RP alone. (4) Conclusions: Neoadjuvant ARSI + ADT combination therapy results in improved pathologic response compared to either alone or none in patients with non-metastatic advanced PCa. Ongoing phase III RCTs with long-term oncologic outcomes, as well as biomarker-guided studies, will clarify the indication, oncologic benefits, and adverse events of ARSI + ADT in patients with clinically and biologically aggressive PCa.

• Keywords
• androgen receptor signaling inhibitors, neoadjuvant therapy, prostate cancer, radical prostatectomy,
• Publication type
• Journal Article MeSH
• Review MeSH

(1) Background: Local therapy is highly promising in a multimodal approach strategy for patients with low-volume metastatic prostate cancer (mPCa). We aimed to systematically assess and summarize the safety, oncologic, and functional outcomes of cytoreductive prostatectomy (cRP) in mPCa. (2) Methods: Three databases were queried in September 2022 for publications that analyzed mPCa patients treated with cytoreductive prostatectomy without restrictions. The outcomes of interest were progression-free survival (PFS), cancer-specific survival (CSS), overall survival (OS), perioperative complication rates, and functional outcomes following cRP. (3) Results: Overall, 26 studies were included in this systematic review. Among eight population-based studies, cRP was associated with a reduced risk of CSS and OS compared with no local therapy (NLT) after adjusting for the effects of possible confounders. Furthermore, one population-based study showed that cRP reduced the risk of CSS even when compared with radiotherapy (RT) of the prostate after adjusting for the effects of possible confounders. In addition, one randomized controlled trial (RCT) demonstrated that local therapy (comprising 85% of cRP) significantly improved the prostate-specific antigen (PSA)-PFS and OS. Overall, cRP had acceptable perioperative complication rates and functional outcomes. (4) Conclusions: Mounting evidence suggests that cRP offers promising oncological and functional outcomes and technical feasibility and that it is associated with limited complications. Well-designed RCTs that limit selection bias in patients treated with cRP are warranted.

• Keywords
• cytoreductive prostatectomy, local therapy, metastatic prostate cancer, prostatectomy,
• MeSH
• Cytoreduction Surgical Procedures * MeSH
• Humans MeSH
• Prostatic Neoplasms * therapy   MeSH
• Prostatectomy MeSH
• Prostate-Specific Antigen MeSH
• Check Tag
• Humans MeSH
• Male MeSH
• Publication type
• Journal Article MeSH
• Systematic Review MeSH
• Names of Substances
• Prostate-Specific Antigen MeSH